Epithelial cells constitute a barrier to drug delivery. For example, the absorption of orally-administered therapeutics may be limited by the gut epithelium, and the absorption of therapeutics delivered by inhalation may be limited by the lung epithelium. Likewise, the absorption of therapeutics delivered to other epithelial sites, such as the rectal cavity, buccal cavity, vaginal cavity, nasal cavity or by topical administration to the skin may be similarly limited by an epithelial barrier. This barrier presents a challenge to the delivery of a wide range of drugs including small molecules, peptides, proteins, vaccines and nucleic acids. Various attempts have been made to mitigate the effect of the barrier to drug absorption provided by epithelia. However, many of those attempts involve the use of agents which either deliberately or as an unintended side effect damage the epithelium. Such damage may result in uncontrolled passage of materials across the epithelium, and that, in possible combination with immunological danger signals resulting from cellular damage, may result in unwanted inflammation of the epithelium. There therefore exists a need for improved technique of assisting the passage of therapeutic agents across an epithelial surface, preferably in a manner which is controlled, temporarily and results in no unacceptable cellular damage (Brayden & Maher (2000) Therapeutic Delivery 1 (1):5-9).
The challenge to drug absorption presented by the epithelium has resulted in some drugs needing to be delivered by routes other than across an epithelium, for example by sub-cutaneous injection. This brings a number of disadvantages including reduced patient acceptability, lower patient compliance and higher costs associated with using and storing liquid formulations, providing injection devices and disposing of used injection devices in a safe and responsible way.
The epithelium provides a barrier to the absorption of drugs because it comprises a layer of cells which are connected to each other by tight junctions which provide a seal against many substances but which can be transiently opened. There exists a need to be able to better control tight junction opening to assist in the delivery of therapeutics. A number of solutions to the problem of opening tight junctions have been proposed. These efforts have led to the identification of two sets of molecules: non-native, extended amino acids (NEAAs) and short-chain fatty acids (SCFAs). NEAAs have been developed primarily by the company Emisphere who have demonstrated marginal improvements in drug uptake but have yet to submit an application for the regulatory approval of a new drug. One SCFA, sodium caprate is used in an approved rectal suppository product to improve the uptake of ampicillin. It is suspected however that the mechanism of improved uptake is through local damage of the mucosal epithelium (Maher et al. (2009) Adv. Drug Deliv. Rev. 61:1427-1449).
There is particular interest in the oral delivery of insulin, glucagon like peptide 1 (GLP-1) and other related molecules for the treatment of diabetics, obesity, suppression of appetite and improvement of carbohydrate metabolism. Such compounds are especially in need of an oral delivery route because they are typically administered for months, years or more, meaning that avoiding injections would significantly increase patient acceptability and potentially lower cost, and also because in nature these gut hormones enter the blood stream of the subject via the hepatic portal vein and delivery across an intestinal barrier would more closely mimic the physiological delivery route.
The present invention is based on the discovery of compounds useful for the controlled opening of epithelial tight junctions.